There are no means for curing advanced breast cancers. Breast cancer has a very high metastatic predisposition to bone. The immense skeletal compartments consisting of 206 bones allow for increasing cancer burden, further metastases, recurrence, cachexia, and eventually, death. In addition, bone metastasis often causes bone destruction, extreme pain, fractures, and paralysis, leading to poor quality of life or death from associated complications. Breast cancer cells not only produce bone-destroying cytokines/chemokines, but also stimulate osteoprogenitor cells to produce factors leading to osteoclastic bone resorption. Although treatments like bisphosphonates and denosumab decrease skeletal events to a certain degree, patients still suffer from skeletal complications and drug side effects such as AVN or atypical fractures. We plan to establish new mechanism-based therapeutic strategies that will reduce cancer burden, prevent skeletal complications, and prolong the life of patients with advanced breast cancers with massive skeletal metastases by effectively killing breast cancers in bone and targeting their osteolytic interactions with bone cells. Our proposal stems from clinical observations. We have consistently observed expression of phosphorylated Extracellular Receptor Kinase (pERK) 1/2 in pathological fracture surgical specimens from patients with breast cancers and well- established aggressive human breast cancer cell lines extensively used in literature. ERK1/2 is downstream of Ras-Raf-MEK1 and is phosphorylated in pathologic conditions such as inflammation and cancers. Our Preliminary Data shed light on a critical role of pERK1/2 in two clinically important angles of bone destruction and cancer cell death. First, breast cancer cells with higher pERK1/2, such as MDA231, cells exhibited more bone destruction than pERK1/2-low breast cancer cells such as MCF-7 following implantation in the proximal tibiae of nude mice. We identified a set of pro-inflammatory cytokines/chemokines that are specifically regulated by pERK1/2 signaling on RT-PCR cytokine/chemokine arrays. Furthermore, breast cancer cells phosphorylate ERK1/2 and trigger expression of cytokines/chemokines in osteoblasts that are co-cultured with breast cancer cells. Second, pERK1/2 targeting alone with AZD6244, a clinical-grade MEK1-pERK1/2 inhibitor, or in combination with doxorubicin increases cell death in breast cancer cells. Our hypothesis is that MEK1-pERK1/2 targeting prolongs the survival of breast cancer-bearing subjects by promoting cancer cell death and blocking pro-osteoclastogenic inflammation in bone. Specific Aim 1 (Mechanism of Bone Destruction) is to determine a pro-osteoclastogenic role of pERK1/2 in aggressive triple-negative breast cancer cells and interacting osteogenic stromal cells. Specific Aim 2 (Mechanistic Enhancement of Cancer Cell Death) is to determine a role of pERK1/2 in breast cancer cell survival and chemoresistance. Specific Aim 3 (Therapeutic Translation in vivo) is to establish pERK1/2 targeting as an effective molecular adjuvant therapy for aggressive osteolytic metastatic breast cancers in bone.